Antigens initiate immune responses and activate the two largest populations of lymphocytes: T cells and B cells. After encountering antigen, T cells proliferate and differentiate into effector cells, while B cells proliferate and differentiate into antibody-secreting plasma cells. These effector cells secrete and/or respond to cytokines, which are small proteins (<about 30 kDa) secreted by lymphocytes and other cell types.
Interleukin-22 (IL-22) is a class II cytokine that shows sequence homology to IL-10. Its expression is up-regulated in T cells by IL-9 or ConA (Dumoutier L. et al. (2000) Proc Natl Acad Sci USA 97(18):10144-9). Further studies have shown that expression of IL-22 mRNA is induced in vivo in response to LPS administration, and that IL-22 modulates parameters indicative of an acute phase response (Dumoutier L. et al. (2000); Pittman D. et al. (2001) Genes and Immunity 2:172). In addition, IL-22 enhances the expression of antimicrobial peptides associated with host defense, including β-defensin, S100A7, S100A8, and S100A. Wolk et al., Immunity, 21:241-54 (2004); Boniface et al., J. Immunol. 174:3695-3702 (2005); Liang et al., J. Exp. Med., 203(10):2271-79 (2006). Taken together, these observations indicate that IL-22 plays a role in inflammation (Kotenko S. V. (2002) Cytokine & Growth Factor Reviews 13(3):223-40).
IL-22 is believed to bind to a receptor complex consisting of IL-22R and IL-10R2, two members of the type II cytokine receptor family (CRF2) (Xie M. H. et al. (2000) J Biol Chem 275(40):31335-9; Kotenko S. V. et al. (2001) J Biol Chem 276(4):2725-32). Both chains of the IL-22 receptor are expressed constitutively in a number of organs. Epithelial cell lines derived form these organs are responsive to IL-22 in vitro (Kotenko S. V. (2002) Cytokine & Growth Factor Reviews 13(3):223-40). IL-22 induces activation of the JAK/STAT3 and ERK pathways, as well as intermediates of other MAPK pathways (Dumoutier L. et al. (2000) supra; Xie M. H. et al. (2000) supra; Dumoutier L. et al. (2000) J Immunol 164(4):1814-9; Kotenko S. V. et al. (2001) J Biol Chem 276(4):2725-32; Lejeune, D. et al. (2002) J Biol Chem 277(37):33676-82).
CRF2 members are receptors for IFNα/β, IFNγ, coagulation factor VIIa, IL-10 and the IL-10 related proteins IL-19, IL-20, IL-22, IL-24, IL-26, as well as the recently identified IFN-like cytokines, IL-28 and IL-29 (Kotenko S. V. (2002) Cytokine & Growth Factor Reviews 13(3):223-40; Kotenko, S. V. et al. (2000) Oncogene 19(21):2557-65; Sheppard, P. et al. (2003) Nature Immunology 4(1):63-8; Kotenko, S. V. et al. (2003) Nature Immunology 4(1):69-77). In addition to these membrane receptors, the CRF2 family also includes a soluble protein, IL-22 binding protein (IL-22BP), which is specific for IL-22 and blocks its activity (Dumoutier, L. et al. (2001) J Immuno/166(12):7090-5; Kotenko, S. V. et al. (2001) J Immunol 166(12):7096-103; Xu, W. et al. (2001) Proc Natl Acad Sci USA 98(17):9511-6; Gruenberg, B. H. et al. (2001) Genes & Immunity 2(6):329-34; Wei C-C et al. (2003) Genes & Immunity 4:204-211). While the IL-22 receptor complex is unique for IL-22, each chain (i.e., IL-22R and IL-10R2) is shared with other CRF2 members to define functional receptors for other cytokines, including IL-20, IL-24 (IL-22R/IL-20R2), IL-28, IL-29 (IFN-λR1/IL-10R2) and IL-10 (IL-10R1/IL-10R2) (Dumoutier, L. et al. (2001) J. Immunol. 167(7):3545-9; Wang, M. et al. (2002) J Biol Chem 277(9):7341-7; Parrish-Novak, J. et al. (2002) J Biol Chem 277(49):47517-23; Kotenko, S. V. et al. (1997) EMBO J. 16(19):5894-903; Spencer, S. D. et al. (1998) J Exp Med 187(4):571-8).
Both chains of the CRF2-composed receptor are necessary for signal transduction. One chain of the composed receptor has been historically defined as a ligand binding chain (e.g., IFNγR1) based on its high affinity for the cytokine. The other chain (e.g., IFNγR2) has been characterized as a helper or accessory chain, and shows minimal affinity for the cytokine alone (Kotenko, S. V. et al. (2000) Oncogene 19(21):2557-65). For IL-22, IL-22R is the high affinity receptor subunit with IL-10R2 subsequently binding to the IL-22/IL-22R complex (Li, J. et al. (2004) Int. Immunopharmacol. 4(5):673-708; Logsdon, N. J. et al. (2002) J. Interferon Cytokine Res 22(11):1099-1112).